Thiophene metabolism

Treiber, A., Dansette, P.M., ElAmri, H., Girault, J.P., Ginderow, D., Mornon, J.P., and Mansuy, D. Chemical and biological oxidation of thiophene Preparation and complete characterization of thiophene S-oxide dimers and evidence for thiophene S-oxide as an intermediate in thiophene metabolism in vivo and in vitro. Journal of American Chemical Society, 1997, 119, 1565. 

A variety of methods have been developed for oxidizing thiophenes to their corresponding thiophene 1-oxides and thiophene 1,1-dioxides, traditionally unstable nonaromatic compounds susceptible to Diels-Alder reactions. A review has appeared discussing the chemistry of thiophene 1-oxides . Evidence for thiophene 1-oxide (82) being a reactive intermediate in thiophene metabolism has been established by the in vivo isolation of the corresponding Diels-Alder adduct 83 . Bulky substituents help stabilize thiophene 1-oxides. For example,... 

Benzo[b]thiophene-2,3-quinone, 5-chloro-oxidation, 4, 824 Benzothiophenes, 4, 863-934 biological activity, 4, 911-913 intramolecular acylation, 4, 761 mass spectrometry, 4, 739 metabolism, 1, 242 phosphorescence, 4, 16 reactivity, 4, 741-861 spectroscopy, 4, 713-740 structure, 4, 713-740 substituents reactivity, 4, 796-839... 

Cripps RE (1973) The microbial metabolism of thiophen-2-carboxylate. Biochem J 134 353-366. 

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

Fig. 7.11. Metabolism of S-(l- [(2,3,4,5-tetrahydro-2-oxothiophen-3-yl)amino]carbonyl ethyl) thiophene-2-carbothioate (MR 889, 7.71) in rats to the active thiol metabolite homocysteine thiolactone thiolactamide (7.72) and to thiophene-2-carboxylic acid (7.73) [154], Subsequent reactions of hydrolysis and conjugation are also shown.

Fig. 8.25 Metabolism of ticlopidine by white blood cells to the reactive thiophene-5-chloride (A) and further breakdown products of this reactive metabolite.

With the exception of 4-methoxydibenzothiophene, which is well characterized, the literature concerning the remaining three mono-methoxy compounds is somewhat confused. As mentioned earlier (Section III, C, 3), dibenzothiophene is metabolized as 1 -hydroxydibenzo-thiophene 5,5-dioxide, which was converted to the corresponding methoxy compound by methylation for structure determination. The position of the methoxy group was determined by the fact that the melting point of the product was different from those of the other three methoxy sulfones, each of which was listed for the first time, but without details of source or preparation. Tilak had attempted the preparation of... 

McMurtry RJ, Mitchell JR. 1977. Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes, including furosemide and cephaloridine. Toxicol Appl Pharmacol 42 285-300. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Pyrantel is quickly metabolized in the body, a small proportion remaining intact by the time it is excreted. Individual metabolites of pyrantel have not been yet identified. Nevertheless, it is known that at least half of them contain the N-methyl-l,3-propanediamine structure of the tetrahydropyrimidyl ring, which is more resistant to the metabolic attack than the thiophene ring (6). 

The metabolism of thiophene (100) was first studied in 1886 by Heffter (1886MI10900), who administered it orally to dogs and noted the increased output of ethereal sulfates in urine. This is typical of aromatic hydrocarbons conversion to phenolic products which are excreted in urine as sulfate conjugates. When fed to rabbits, there was no increase in the ethereal sulfate output, but there was some indirect evidence of the presence in urine of dihydrodiols and thienylmercapturic acids (45MI10900). This was confirmed by Bray and coworkers (71MI10906,68BJ(109)11P>, who studied thiophene and benzothiophene metabolism in rabbits and rats. The only identifiable metabolites in urine were the thienylmercapturic acids (101) and (102), which are probably formed via conjugation of the intermediate... 

The above paragraphs summarize some of the studies in this area, and indicate that in preparing potentially useful biologically active agents of all classes, thiophene and ben-zothiophene rings may replace benzene, naphthalene or indole rings to produce active compounds which may be less toxic, have different physiological disposition and/or different modes of metabolism or detoxification, and thus impart desirable properties. 

In addition to providing spectroscopic models, the oxidation of quinoxaline-substituted molybdenum and tungsten 1,2-enedithiolates has yielded the corresponding 3-sulfido-thienoquinoxaline (thiophene-containing) derivatives (Figure 19) [172,173], This transformation models the oxidative conversion of MPT to form B and the metabolic conversion of MPT to urothione [37,49],... 

Thiophenes. Although several attempts have been made to demonstrate the aerobic degradation of thiophene, none have succeeded (39-41). However, the anaerobic metabolism of thiophene was reported by Kurita et al. (42). Hydrogen sulfide was released from thiophene when bacterial cultures, obtained from oil sludges, were grown with polypeptone. The fate of the carbon atoms was not determined but they could not be found as lower hydrocarbons (C to C4). 

Benzothiophene. There have been several reports on the aerobic co-metabolism of benzothiophene (42, 46, 47). Bohonos et al. (46) identifed some benzothiophene metabolites by GC-MS and the structures of these are shown in Figure 8. Although the only compounds found were oxidized on the thiophene ring, they could not exclude the possibility of oxidation of the benzene ring. Finnerty et al. (48) found that benzothiophene was transformed to unidentified water-soluble products by a dibenzothiophene-oxidizing bacterium. 

Figure 10. Simplification of the proposed pathways from dibenzothiophene co-metabolism by pure cultures of aerobic bacteria. (I) dibenzo-thiophene-sulfoxide, (II) 1,2-dihydroxydibenzothiophene, (III) 3-hydroxy-2-formylbenzothiophene.

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

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